NM_004563.4:c.73C>G

Variant names:

• chr14-24096935-C-G
• rs769558514
• NM_004563.4:c.73C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004563.4(PCK2):​c.73C>G​(p.Arg25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PCK2 NM_004563.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 0 publications found

Genes affected

PCK2 (HGNC:8725): (phosphoenolpyruvate carboxykinase 2, mitochondrial) This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2014]

NRL (HGNC:8002): (neural retina leucine zipper) This gene encodes a basic motif-leucine zipper transcription factor of the Maf subfamily. The encoded protein is conserved among vertebrates and is a critical intrinsic regulator of photoceptor development and function. Mutations in this gene have been associated with retinitis pigmentosa and retinal degenerative diseases. [provided by RefSeq, Jul 2008]

NRL Gene-Disease associations (from GenCC):

• retinitis pigmentosa 27

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• enhanced S-cone syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34464893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004563.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK2	NM_004563.4	MANE Select	c.73C>G	p.Arg25Gly	missense	Exon 2 of 10	NP_004554.3	A0A384MTT2
	NRL	NM_001354768.3	MANE Select	c.-27-14060G>C		intron	N/A	NP_001341697.1	P54845-1
	PCK2	NM_001018073.3		c.73C>G	p.Arg25Gly	missense	Exon 2 of 7	NP_001018083.2	Q16822-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK2	ENST00000216780.9	TSL:1 MANE Select	c.73C>G	p.Arg25Gly	missense	Exon 2 of 10	ENSP00000216780.4	Q16822-1
	PCK2	ENST00000396973.8	TSL:1	c.73C>G	p.Arg25Gly	missense	Exon 2 of 7	ENSP00000380171.4	Q16822-2
	NRL	ENST00000561028.6	TSL:2 MANE Select	c.-27-14060G>C		intron	N/A	ENSP00000454062.2	P54845-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.062
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0	B
Vest4		0.55
MutPred		0.36		Gain of loop (P = 0.0013)
MVP		0.50
MPC		0.098
ClinPred		0.71	D
GERP RS		3.7
Varity_R		0.44
gMVP		0.72
Mutation Taster		=276/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769558514; hg19: chr14-24566144;